Strategies for Optimizing Treatment Outcomes

The relationship between increased levels of cholesterol and elevated risk for coronary heart disease (CHD) has been described in many epidemiological and well-designed prospective trials. Additionally, since first being elucidated by the Coronary Primary Prevention Trial, numerous trials have demonstrated that reducing blood cholesterol levels results in a corresponding reduction in risk for CHD. The evidence now indicates that cholesterol reduction confers up to a 35% reduction in total mortality, coronary mortality, coronary artery procedures, stroke, and other CHD-related events. This article reviews data that demonstrate that cholesterol reduction decreases CHD risk, discusses current and emerging treatment modalities, describes methods by which health care practitioners can enhance lipid treatment outcomes, and identifies educational tools that can be used to empower patients to improve their compliance and become actively involved in reducing their CHD risk.

B ased on the decline of the death rate from coronary heart disease (CHD) over the past 10 to 15 years, it appeared as if public health efforts aimed at reducing cigarette smoking and implementing lipid modification through dietary changes and statin use were having a positive effect on cardiovascular health. However, the data can be misleading because despite the reduction in CHD mortality, hospitalization rates for myocardial infarction (MI) and other CHD events continues to rise. 1 Upon closer inspection, it appears the decline in CHD deaths is attributable to an improvement in peri-event procedures and care such as coronary artery bypass graft surgery and angioplasty. Furthermore, the increasing number of CHD-related hospitalizations may be associated with a rapid increase in the prevalence of other CHD risk factors such as an aging population, the growing number of overweight Americans, the increased prevalence of diabetes, and hypertension. These observations may explain the persistence of CHD as the leading cause of death among Americans and suggest that renewed effort is required to reduce the cardiovascular risk burden within the U.S. population. Data from the Framingham Heart Study demonstrate a direct correlation between cholesterol levels and 40-year survival among adults younger than 50 years. 2 Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for the development of CHD, and clinical trials have demonstrated a reduction in risk with LDL-C-lowering therapy.

■■ Cholesterol and CHD Risk
Atherosclerosis results from the accumulation of LDL-C in the subendothelial space of the arterial walls. Over time, this accumulation leads to the formation of atherosclerotic lesions. Large lesions are relatively stable but can cause obstructive symptoms such as angina pectoris. These lesions can be effectively treated with coronary artery bypass graphs, angioplasty, or stents. Surprisingly, it is the small newer lesions that are more prone to rupture and can result in the formation of a thrombus that can lead to MI, unstable angina, sudden death, stroke, or occlusion of a peripheral artery.
The Framingham Heart Study 3 was the first to propose that the risk of developing CHD was linked to cholesterol, a concept that has been subsequently confirmed in numerous trials. The Framingham study was a prospective epidemiological trial that monitored blood lipids, blood pressure, smoking, and exercise habits in men and women over a period of time, up to 28 years. A continuous, graded relationship between increasing cholesterol levels (total and LDL) and CHD risk was observed. Moreover, the results proposed that high-density lipoprotein cholesterol (HDL-C) levels were inversely associated with CHD risk. Data from the Framingham study forms the basis of the CHD risk assessment advocated by Adult Treatment Panel III (ATP III).
The hypothesis that cholesterol levels are associated with risk of CHD was further confirmed in the Multiple Risk Factor Intervention Trial (MRFIT). MRFIT demonstrated a curvilinear relationship between rising cholesterol levels and CHD risk. Risk increased slightly as total cholesterol levels rose from 150 mg/dL to 200 mg/dL, at which point, risk increased 2-fold at cholesterol levels of 250 mg/dL, and 4-fold at levels >300 mg/dL. 4

■■ Outcome Trials
The first large study demonstrating that interventions that reduce cholesterol lead to a reduction in CHD morbidity and mortality was the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). The LRC-CPPT randomized men with primary hypercholesterolemia to receive cholestyramine or placebo daily for an average of 7.4 years. The cholestyramine group showed a 9% reduction in CHD mortality and nonfatal MI. These benefits were most strongly linked to a decrease in total and LDL cholesterol. LRC-CPPT also provided one of the earliest demonstrations of the principle that every 1% reduction in LDL-C leads to a 2% reduction in CHD risk. 5 Since publication of the LRC-CPPT results, numerous clinical trials have added evidence from a variety of patient populations using several different lipid-lowering therapies ( Table 1). The Scandinavian Simvastatin Survival Study (4S) study showed a reduction in mortality and morbidity in CHD patients with high total and LDL-C levels. This trial was also the first to show a reduction in overall mortality with lipid-lowering therapy. 6 The West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated a reduction in CHD risk in patients with elevated cholesterol but with no CHD at enrollment. 7 Subsequently, the Cardiac and Recurrent Events (CARE) trial and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) showed that CHD risk could be reduced in patients who had normal or near-normal cholesterol levels. 8 CARE provided evidence of benefit in a secondary prevention setting whereas AFCAPS/TexCAPs was in a primary prevention population. The Heart Protection Study demonstrated a significant reduction of the CHD risk in a large population of patients with CHD and CHD risk equivalents and only moderately elevated LDL-C (Table 2). 9 Although the bulk of recent evidence that demonstrates the benefits of lipid-lowering therapy on CHD outcomes is derived from statin intervention trials, other drugs have also proven beneficial. The Helsinki Heart Study showed a reduction in CHD risk with gemfibrozil. 10 More recently, the Veterans Affairs High-Density Lipoprotein Intervention Trial demonstrated a benefit with gemfibrozil in patients who did not have elevated total cholesterol or LDL-C but had low levels of HDL-C. Patients receiving gemfibrozil showed no significant change in LDL-C although their HDL-C was raised by 6%. 11

■■ Current Treatment Modalities
The ATP III recommendations retain the historical endorsement of therapeutic lifestyle changes (TLC), primarily dietary modification, and regular exercise, as essential elements of risk-reduction therapy. ATP III advocates a 3-month trial of TLC before initiating drug therapy, although some high-risk patients will require pharmacologic intervention from the outset. TLC is intended to reduce CHD risk by helping to decrease LDL-C and triglyceride levels and raise HDL-C.
Diet modification is the cornerstone of therapy for mild to moderate dyslipidemia. ATP III recommends a TLC diet that includes a reduction of saturated fats to <7% of total calories, reduction of intake of dietary cholesterol to <200 mg/day, addition of plant sterols/stanols at a level of 2 g/day (plant sterols/stanols are commercially available in special margarines), and incorporating viscous fiber into the diet at a level of 10 g to 25 g/day. 12 If followed faithfully, dietary therapy can result in a reduction in total cholesterol of 12% to 18%. 13 There is no clear evidence that demonstrates a diet low in saturated fat and cholesterol will improve CHD outcomes. Systematic reviews of observational studies have found that increased consumption of fruits and vegetables is associated with a lower incidence of MI and stroke; however, these data are limited. Patients who do not respond to the recommended diet changes or who have difficulty complying with recommendations should be referred to a dietician or nutritionist for medical nutrition therapy.

Landmark Primary Prevention
Cholesterol-Lowering Trials  Persistent physical inactivity is now recognized by the American Heart Association as an independent risk factor, raising the risk of CHD by 2-fold. Physical activity raises HDL-C levels and decreases the concentration of very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides. When exercise results in weight loss, it contributes to LDL-C reduction. Weight reduction can reduce LDL-C levels and ameliorate the risk factors associated with the metabolic syndrome by improving insulin sensitivity and serum glucose uptake and thus reducing the risk of diabetes. Cigarette smoking remains a CHD risk factor and smoking cessation can contribute to an increased HDL-C.
Failure of TLC to modify LDL-C or the presence of high CHD risk warrants the use of pharmacologic therapy. However, TLC should be maintained and continually reinforced by the physician even after the initiation of drug therapy. Treatment goals and lipid thresholds for initiating drug therapy are dependent on the patient' s risk category that is calculated using the Framingham risk assessment tool advocated by ATP III.
Risk category 1 includes patients with a 10-year risk >20% (e.g., definite CHD or CHD risk equivalents). For these patients, the LDL-C threshold for initiating therapy is >130 mg/dL (after a 3-month trial of TLC) and the treatment goal is <100 mg/dL. For patients whose LDL-C cholesterol level is 100 mg/dL to 129 mg/dL, drug therapy is optional and physicians are encouraged to use their clinical judgment to determine if drug therapy is appropriate. Recently published data from the Heart Protection Study, however, have led many experts to reduce the threshold for drug therapy in patients with established CHD and CHD risk equivalents to >100 mg/dL. Risk category 2 encompasses patients without definite CHD or CHD risk equivalents but with at least 2 major risk factors that confer a 10-year risk of <20%. For patients with a 10-year risk of <10%, the LDL-C threshold is >160 mg/dL and the target is <130 mg/dL. In those patients that present with a 10-year risk of 10% to 20%, the treatment threshold is >130 mg/dL and the target is <130 mg/dL. In both instances, lipid-modifying drug treatment may not be necessary after a 3-month trial of TLC.
Risk category 3 includes patients without CHD who have 0 to 1 major risk factor. Drug treatment should be considered for these patients if their LDL-C is >190 mg/dL after 3 months of TLC. For patients in this category, the LDL-C goal is <160 mg/dL. When setting therapeutic goals in patients with metabolic syndrome, physicians must consider up to 3 lipoprotein abnormalities, including increased LDL-C, increased triglycerides, and low HDL-C. These patients should be provided a 3-month trial of TLC. If the lipid profile is not favorably altered by TLC, an agent that reduces LDL-C and possibly triglycerides should be added to the lifestyle therapy. For high-risk patients with elevated triglycerides (>200 mg/dL), drug therapy can be added if weight reduction and increased physical activity fail to have a triglyceride-lowering effect.
LDL-C-lowering drug therapy should be monitored at 6-week intervals to determine if progress is being made toward goal, evaluate patient tolerability and adherence to the therapy, and provide patient education. If the LDL-C goal is not achieved, therapy should be intensified, with an increase in the drug dose or the addition of a second LDL-C-lowering drug with a different mechanism of action. Even if the LDL-C goal is attained, physicians and patients are encouraged to identify and treat other CHD risk factors such as hypertension or diabetes. Once the LDL-C levels are within a desirable range, patients should be monitored every 6 to 12 months for any event that may impact compliance to therapy.

■■ Improving Lipid-Therapy Outcomes
The ATP III guidelines offer the opportunity to take significant steps in reducing the risk of CHD among Americans. However, the challenge is in the implementation of the guidelines. Successful implementation leads to increased adherence and, ultimately, better clinical and economic outcomes. In general, physicians recognize the importance of lipid control and are familiar with the basics of the guidelines. However, fewer than 40% of dyslipidemic patients are being treated, and many who are being treated are not reaching their target goals. Fewer than half of primary prevention patients have LDL <130 mg/dL, and fewer than 20% of patients with CHD who receive treatment have an LDL-C <100 mg/dL. Persistence with therapy is another challenge, as 70% of patients do not maintain therapy beyond one year. 14 Noncompliance is not always the result of patient misunderstanding or intransigence. Health care professionals share the responsibility for assisting patients in their attempts to reach therapeutic goals. Among the reasons physicians do not adhere to guidelines are lack of awareness; disagreement with the guidelines; a perception of uncertain outcomes; a practice setting not conducive to implementation; and environmental factors, including lack of reminders and ineffective educational materials. Managed care • Target and enroll at-risk patients • Reduce patient noncompliance • Address patients on multidrug regimens who still fail to reach goals • Manage existing comorbid conditions that prevent prescription of optimal lipid-lowering therapy • Enhance adherence to guidelines • Well-conceived, managed and operated cost-effective clinics Steps to Improve the Cost-Effectiveness of Lipid-Modifying Therapy pharmacists can assist in the effort to promote lipid screening and effective lipid management as a priority by assisting in the development of clinical programs designed to identify and track high-risk patients, providing educational seminars on the benefits of lipid-lowering therapies, communicating to physicians the nature of the pharmacy benefit design and the cost-effectiveness of different therapies, and educating patients to prompt their doctors to screen for CHD (Table 3).

Elements of a Successful Lipid Management Program
Patients who need lipid-lowering therapy are likely to need it long-term, perhaps for a lifetime. Yet, many patients do not adhere to their lipid-modification regimen even when prescribed an effective, well-tolerated agent. Improving adherence to therapy requires empowering patients, encouraging physicians, and establishing new ways to deliver lipid-modifying care. Clearly, there are numerous reasons patients discontinue therapy. Consequently, there is no single strategy that will improve adherence in all patients.
Perhaps the best strategy may be to employ a systematic approach of providing education about the disease and encouraging patients to take increased responsibility for their own care. Pharmacists can work closely with physicians to provide educational opportunities that teach patients about cardiovascular risk factors and explain the potential benefits of therapy. In addition, pharmacists are instrumental in increasing adherence through refill reminders, answering questions about drug interactions and side effects, and encouraging patients to follow up with their physicians on a regular basis. Tools that can support this effort include the Internet, videos, informational brochures, and telemedicine. Additionally, pharmacists should encourage the involvement of family and friends in the treatment plan, schedule more frequent visits, strive to keep the treatment regimen as simple as possible, provide clear instructions, and discuss adherence for at least a few minutes at each visit. Special attention should be given to those patients who do not reach goals, who miss appointments, or who require complex therapeutic regimens to reach treatment goals.
Adherence is also improved by devising new avenues of CHD risk screening, therapy, and patient education. Targeting inpatients during hospitalization for either an acute coronary event or an interventional procedure is an effective way to identify the highestrisk patients and initiate appropriate therapy prior to discharge. Multidisciplinary lipid-management clinics that address many aspects of CHD have proven to be effective in increasing adherence and improving both clinical and economic outcomes, particularly when treating patients at highest risk (Table 4). Hospitaland clinic-based pharmacists can also collaborate with community pharmacists to identify, educate, and treat high-risk patients.

■■ Summary and Conclusions
The ongoing challenge in health care is to encourage pharmacists, physicians, and patients to employ strategies that lead to improved clinical and economic outcomes. Adherence to the ATP III guidelines is critical to reproducing the magnitude of CHD risk-reduction benefit demonstrated in clinical trials of lipid lowering. A significant effort must be made to maximize compliance in order to attain the highest possible level of CHD risk reduction. Pharmacists can impact patient care at all levels by encouraging cholesterol screening and management. Whether in the clinic, hospital, or in the pharmacy, pharmacists have the opportunity to assist patients in achieving their lipid targets, encouraging risk factor intervention, monitoring therapies, and encouraging both adherence and persistence with treatment.